Gout is severe disease accompanying various symptoms such as arthritis (gout attack), gouty tophus, urinary calculi or the like. Gout is deeply associated with lifestyle habit, and in Japan, this disease was rarely found before 1960, but increased with high-growth of the economy and at present, it is said that more than six hundred thousand patients are suffering from this disease. Conventionally, age of onset of gout was in fifties, but at present, a peak age thereof onset is moved to thirties, and age of onset tends to shift to younger generation. Further, hyperuricemia that is a basic pathology of gout has been increasing. It is reported that when serum uric acid level is elevated, risk for ischemic heart disease as well as gout is increased.
Pathologic conditions of hyperuricemia fall into two categories; an uric acid production promotion type and an uricosuric suppression type. Ratio of each of types among all patients with hyperuricemia is said to be approximately 20% for uric acid production promotion type, approximately 60% for uricosuric suppression type, and approximately 20% for combination of the two. At present, use of allopurinol that is xanthine oxidase inhibitor is recommended for the former and benzbromarone that is uricosuric agent is recommended for the latter. At least 20 years have passed since both drugs were released and for allopurinol, side effects such as hepatic disorder (including fulminant hepatitis), bone-marrow suppression, severe dermatitis or the like are reported so far; for oxypurinol that is a metabolite of allopurinol, it is reported that blood disorder and hepatic disorder are caused in dialysis patients due to accumulation of this drug at high-level in the body. For benzbromarone, hepatic disorder (including fulminant hepatitis) is reported. In view of the foregoing, developments of new drugs with the least side effects have been desired.
For uricosuric agent, those in which benzofuran skeleton of benzbromarone is left and side-chain portions are chemically modified in various ways are reported (see Patent Documents 1 to 4). Further, for uricosuric agent one using a compound having nonpeptide angiotensin II receptor antagonistic action (see Patent Document 5), one using dihydropyridine derivatives (see Patent Document 6), one using hydantoin derivatives (see Patent Document 7), one using biaryl compounds or diaryl ether compounds (see Patent Document 8), or the like are reported.
Besides, for xanthine oxidase inhibitor for suppressing the production of uric acid, one using pyrazolo-triazine derivatives (see Patent Document 9), one using 3-phenylpyrazole compounds (see Patent Document 10), one using 1-phenylpyrazole compounds (see Patent Document 11), one using Filipendula ulmaria that is rosaceous perennial (General name; meadowsweet), one using quercetin-4′-glycoside and quercetin-3-glycoside isolated therefrom (see Patent Documents 12 and 13), one using 2-phenylthiazole derivatives (see Patent Document 14), one using plant body selected from Origanum valgare, Mosla chinensis, Elsholtzia ciliata, Elsholtzia patrini, Elsholtzia splendens, Melissa officinalis, Rosmarinus officinalis, Mentha spicata, Mentha x piperita, Satureja montana, Piper betle and Ehretia microphylla, and/or extracts of the plant body (see Patent Document 15), or the like are reported.
In addition, as new type of therapeutic agent for hyperuricemia, one using a insulin resistance improved substance such as thiazolidinedione compounds or the like (see Patent Document 16), one relating to prophylactic and therapeutic agent for hyperuricemic disorder containing monoene acid having a carbon number of 20 and/or derivative thereof, and monoene acid having a carbon number of 22 and/or derivative thereof as the active ingredient (see Patent Document 17), one relating to uric acid level depressant containing extracts from ginkgo biloba as the active ingredient (see Patent Document 18), one relating to treatment of hyperuricemia or prophylactic composition containing chondroitin sulfuric acid protein conjugate as the active ingredient (see Patent Document 19) or the like are reported.
Of them, several novel xanthine oxidase inhibitors, domestically and abroad, are already in their development stage, while for uricosuric agents, no movement of the development has been seen worldwide, and for the sake of improvements of QOL of patients with hyperuricemia, developments of new uricosuric agents with the least side effects have been desired.
In the meantime, benzbromarone represented by the following formula is;

is one type of benzofuran derivatives, and has been used extensively for long years due to its potent uricosuric effect. As for drug metabolism of benzbromarone, in the report (see Non-patent Document 1) for human patients disclosed in 1972, it was considered that benzbromarone is debromination metabolized in the liver, and is metabolized to bromobenzarone lacking one bromine or to benzarone lacking two bromine. However, later research revealed that metabolic products of benzbromarone is not debrominated substances, but primarily hydroxides in which first position or sixth position of benzofuran ring is hydrated (see Non-patent Document 2 to 6). It has also been suggested that as for persistence of uricosuric action of benzbromarone, metabolic products in the blood may be involved (see Non-patent Document 5).
Further, onset of severe hepatic disorder in patients taking benzofuran derivatives such as benzbromarone, benzarone, benziodarone or the like has been reported, and possibility that metabolic products common to these drugs might be associated with manifestation of hepatic disorder has been pointed out. Particularly, since benzarone is a dehalogenated substance of benziodarone and benzbromarone, the possibility that benzarone itself may trigger hepatic disorder has not been denied completely yet.
As discussed above, many researches have been made on metabolic products of benzofuran derivatives such as benzbromarone, benzarone, benziodarone or the like and side effects thereof, therapeutic agent or prophylactic agent for hyperuricemia which does not cause severe hepatic disorder, is highly safe, and has potent uricosuric action have not been developed at the present moment.    Patent Document 1: Japanese Patent Application Laid-Open (JP-A) No. 59-73579    Patent Document 2: JP-A-1-216984    Patent Document 3: JP-A-3-261778    Patent Document 4: JP-A-6-184132    Patent Document 5: JP-A-5-25043    Patent Document 6: JP-A-5-279255    Patent Document 7: WO 97/02033    Patent Document 8: JP-A-2000-1431    Patent Document 9: JP-A-6-316578    Patent Document 10: JP-A-10-310578    Patent Document 11: WO 98/18765    Patent Document 12: JP-A-2002-121145    Patent Document 13: JP-A-2003-171283    Patent Document 14: JP-A-2002-105067    Patent Document 15: JP-A-2003-252776    Patent Document 16: JP-A-11-255669    Patent Document 17: JP-A-2001-278786    Patent Document 18: JP-A-2002-212085    Patent Document 19: JP-A-2003-335698    Non-patent Document 1: Broekhuysen, J., et al., Eur. J. Clin. Pharmacol., 4, 125-130 (1972)    Non-patent Document 2: Walter-Sack, I., et al., Eur. J. Clin. Pharmacol., 39, 577-581 (1990)    Non-patent Document 3: De Vries, J. X., et al., Clin. Investig., 71, 947-952 (1993)    Non-patent Document 4: De Vries, J. X., et al., Xenobiotica, 23, 1435-1450 (1993)    Non-patent Document 5: Walter-Sack, I., et al., Eur. J. Med. Res., 1, 16-20 (1995)    Non-patent Document 6: Walter-Sack, I., et al., Eur. J. Med. Res., 3, 45-49 (1998)